Osteoporosis and bone-demineralizing disorders (e.g. osteomalacia) are skeletal diseases that cause decreased bone mineral density and reduce the mechanical competence of bone, predisposing to fractures. Whereas osteoporosis is a structural bone disease where both bone mineral and matrix are lost, bone- demineralizing disorders involve a deficit in bone mineral only. Therefore, the ratio of bone constituent densitie (RBCD), given as the ratio of bone mineral density to bone matrix density, would be a suitable metric by which to distinguish these two groups of diseases. The RBCD is closely related to the degree of mineralization of bone (DMB), which is expressed as mass of mineral per volume of matrix. Current diagnostic methods, such as dual-energy x-ray absorptiometry (DXA), measure only bone mineral density and, thus, are unable to distinguish between these two groups of diseases. Secondary diagnostic methods, such as bone biopsy, can sometimes discriminate between these diseases, but this procedure is invasive. Because these two disorders often co-occur in the elderly, such patients are often misdiagnosed as having only osteoporosis, leaving their bone-demineralizing disorder untreated. The proposed work builds on recent research conducted in the applicant's lab. This project seeks to adapt MRI-based methods for bone matrix and mineral density measurements, proven on animal specimens in specialized hardware, into a single quantitative examination that can be performed on humans. The hypothesis is that the proposed examination will be able to distinguish between osteoporosis and disorders of impaired mineralization using clinical MRI equipment and without the risks associated with ionizing radiation, as in DXA or quantitative computed tomography (QCT), or invasive bone biopsy. The proposed work will include determining the optimal magnetic field strength for this procedure, the method for isolation of bone matrix-associated proton signal from the total bone proton pool, the adjustment of the MRI pulse sequence to balance image resolution with scan time, the design of image intensity reference samples, and the improvement of algorithms used to calculate densities from image intensities. The resulting examination will then be applied to normal and chemically demineralized bone specimens in order to confirm the method's accuracy and reproducibility. The true densities of these specimens will be measured by gravimetry. The final step will be to translate this method to the clinic in a small pilot study involving healthy volunteers and subjects with these two different classes of disorders in order to demonstrate the method's feasibility to distinguish between disease states. PUBLIC HEALTH RELEVANCE: Osteoporosis is a bone disorder that afflicts 10 million adults in the United States. This disorder mimics bone- demineralizing disorders on the standard clinical diagnostic scan, dual energy x-ray absorptiometry (DXA), and so bone-demineralizing disorders are often misdiagnosed as osteoporosis, which is vastly more prevalent in the elderly. The proposed research seeks to prove the feasibility of an MRI-based method which can readily distinguish between osteoporosis and disorders of impaired mineralization based on measurement of both bone mineral and matrix densities without the use of ionizing radiation or invasive bone biopsy.